L5: Carcinogenesis of Cancer Flashcards
List the categories of agents known to cause cancer and give specific examples.
- Infectious - such as HPV and uterine cancer
- Radiation will increase the risk of many cancers especially haematological cancers due to the high turnover
- Chemicals
- Minerals e.g. asbestos and heavy materials
- Physiological such as oestrogens, androgens and obesity
How do cells normally protect the integrity of the genome?
There are many mechanism that go onto prevent cancer developing:
- Antioxidants found in fruit which act against free radicals (these rip open DNA and cause mutations)
- Detoxification at the liver
- DNA repair mechanisms
- Apoptosis
Immune system which can identify normal cells
Some carcinogens require metabolic activation such as through the cytochrome P450 proteins. These however have polymorphisms. The will be activated to a different extent in different patients. Some patients may be less/more effective detoxification mechanisms, repair mechanisms etc. This is why not everyone exposed to the same carcinogens will go onto to develop cancer.
Give examples of common genetic abnormalities seen in tumours.
Common genetic abnormalities that can occur as a result to the initial insult:
- Base pair substitution - Frameshift - Deletion or insertion - a whole exon may be deleted or inserted - Gene amplification e.g. seen in breast cancer in HER2 - Chromosomal translocations - common in sarcomas where big chunks of chromosomes will become detached and attach to the wrong chromosome e.g. Philadelphia chromosome - Chromosomal inversion - Aneuploidy
The consequences of mutations could be nothing, gain of function (activation or proto-oncogenes) or loss of function (inactivation of tumour suppressor genes).
These often do not occur in isolation. Both of these together lead to cancer development.
Define a carcinogen.
A carcinogen is any agent that will significantly increase the risk of developing cancer.
Describe the steps involved in carcinogenesis.
- Initiation is the first instance of chemical modification of DNA. There may not be cancer yet but initiation has taken place.
- Replication - mutation becomes fixed in the cells
- Growth of the clone
- Cluster of mutated cells
We need promotion as well as initiation for the carcinogenesis pathway to take place.
How does epigenetics affect CpG islands?
Upstream of the promoter region we see many CG repeats (CG islands) in around 70% of genes. The p is the phosphorylation between them. DNA methyltransferases will come and methylate the C changing the structure of the DNA, this means that transcription cannot take place as the apparatus cannot bind.
What is the cause of Xeroderma pigmentosum?
Xeroderma pigmentosa (XP) the patient is very sensitive to UV light as they have damaged repair proteins responsible to fixing the damage it causes. They are more likely to go on to develop skin cancers. Bonds form between adjacent nucleotides due to UV light causing a bulk, and the structure affecting protein expression. This is due to a mutation in a nucleotide-excision repair protein.
What is the cause of Hereditary Non-Polyosis Colonic Cancer?
Hereditary Non-Polyposis Colorectal Cancer (Lynch syndrome) - Patients inherit faulty mismatch repair proteins. They only have one correct mismatch repair protein and so if another one gets knocked out, they will develop colorectal cancer. Patients with this often have prophylactic colectomies as they are such a high risk of colorectal cancer.
What is the cause of Ataxia telangiectasia?
Ataxia telangiectasia (AT) is a hereditary condition characterized by progressive neurologic problems that lead to difficulty walking and an increased risk of developing various types ofcancer. Signs of AT is often develop in childhood. This is due to a faulty recombinational repair protein.
How does smoking cause cancer?
Contains over 150 carcinogens that can cause mutations.
How can alcohol cause cancer?
Alcohol is another carcinogen. It has been linked to many cancers such as oral, oesophageal, bowel and liver.
• Converted into acetaldehyde - can cause DNA damage
• Increases levels of oestrogen and testosterone
• Increases uptake of carcinogenic chemicals into cells within the upper GI
• Reduces levels of folate, needed for accurate DNA replication
Can kill surface epithelium leading to unscheduled proliferation
How can chronic inflammation lead to cancer?
Chronic inflammation is associated with many different cancers. Inflammatory response causes:
• DNA damage from free radicals released by immune cells (initiation)
• Growth factor induced cell division to repair tissue damage leads to promotion
These can contribute to the development of cancer.
An example includes: Barret’s Oesophagus - chronic inflammation. The cells have undergone metaplasia - from squamous cell epithelium to glandular epithelium. There is therefore an increased of the glandular epithelium becoming cancer.
What is the correlation between the turnover of cells and the chance of developing cancer?
The more the cell divide the more likely errors are incorporated overtime and the risk of cancer increases. For example BCC - the basal cells are constantly dividing and replacing skin, they are more likely to get errors incorporated. Colorectal cancer is also common as the lining is replaced every week. Bone replicated rapidly in childhood but not as adults as a result it is common in children but not so much in adults.
What is a pro-carcinogen?
Some carcinogens will be direct acting on DNA such as free radicals, nitrosamines, UV light and ionising radiation.
There are also procarcinogens which require enzymic (metabolic) activation before acting on DNA such as aromatic amines, polycyclic aromatic hydrocarbons (PAHS).
What are cancer predisposition syndromes?
Cells are constantly being exposed to damaging agents but they do not all go onto to become cancer. There is repair processes to fix the errors. Repair proteins scan the DNA looking for errors in DNA coding. Some patients can inherit faulty copies of these genes and so as a result they are susceptible to cancer as if a change occurs there is no repair process to fix it. These are known as the cancer predisposition syndromes.
